Author ORCID Identifier

0000-0002-7351-5924

Date of Graduation

8-2020

Document Type

Thesis (MS)

Program Affiliation

Cancer Biology

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Mikhail G. Kolonin, Ph.D.

Committee Member

Sendurai A. Mani, Ph.D.

Committee Member

Gheath Al-Atrash, D.O., Ph.D.

Committee Member

Wenliang Li, Ph.D.

Committee Member

Naoto T. Ueno, M.D., Ph.D.

Abstract

Cancer metastasis is the principal cause of most cancer-associated morbidities. While radiotherapy, hormone therapy, and novel therapeutic strategies, including immunotherapy, have shown promise in inhibiting tumor growth, chemotherapy remains the mainstay in the clinical management of metastatic progression. This is often the case in triple-negative breast cancer (TNBC), an aggressive breast cancer subtype where tumorigenesis is independent of HER-2, progesterone, or estrogen receptor expression. Despite improving TNBC prognosis, recent studies report that after chemotherapy administration, TNBC drug-tolerant tumor cell survival, relapse, and metastatic dissemination may be promoted. Overcoming drug resistance exhibited by metastatic tumor cells is a challenge owing to the lack of specific biomarkers and the absence of drugs available to selectively target them. The development of such therapeutics would be pivotal for cancer medicine, as they would enable targeted ablation of the mortality-responsible tumor cell population with minimal off-side effects.

Our studies indicate that in TNBC mouse models, the chemotherapeutic agent cisplatin exacerbates spontaneous metastases to the lung. In this project, we have aimed to develop novel compounds that specifically target chemoresistant cancer metastases. It is based on the hypothesis that metastatic cancer cells express unique cell surface receptors that can be targeted. To test this hypothesis, we performed a combinatorial phage-displayed peptide library screen to isolate phage-displayed cyclic peptides that mimic the natural ligands of novel receptors expressed by chemoresistant metastatic TNBC tumor cells. These peptides were termed Breast Lung Metastasis Peptides (BLMPs), owing to their pulmonary metastases-specific tropism. Two lead BLMPs were validated in murine cancer models in vivo and in vitro. We demonstrate that BLMP homing to pulmonary metastases was independent of chemotherapy administration. Our findings suggest that the BLMPs localized predominantly along the invasive edges of the pulmonary metastases. Immunofluorescence assays suggest that the two lead BLMPs are selective for tumor cells exhibiting a mesenchymal phenotype. BLAST sequence analysis of the two lead BLMP peptides reveals that they bear homology with biological ligands of receptors implicated in EMT activation and metastatic progression. To explore the therapeutic potential of these metastatic tumor cell- specific peptides, the BLMPs were modified to generate hunter-killer peptides (HK-BLMPs) that induce apoptosis upon internalization into targeted cancer cells. We demonstrated that one of the HK-BLMP peptides selectively kills cancer cells and shows potential in decreasing metastatic burden in a murine model of spontaneous TNBC metastasis.

Keywords

Chemotherapy, Chemoresistance, Triple-Negative Breast Cancer, Metastasis, Epithelial to Mesenchymal Transition, Phage Display Technology, Peptides, Anti-metastasis therapy

Available for download on Saturday, July 24, 2021

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